Prospects for extending healthy life - a lot

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Prospects for extending healthy life - a
lot Aubrey D.N.J. de Grey, Ph.D. Chairman and
CSO, Methuselah Foundation Lorton, VA, USA and
Cambridge, UK Email aubrey_at_sens.org MF site
http//www.methuselahfoundation.org/ Science
site http//www.sens.org/ Prize site
http//www.mprize.org/
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Shameless plug
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Why I am doing this
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Fun Not fun
Why I am doing this
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• Structure of this talk
• Repair versus retardation
• Longevity escape velocity concept
• Some evidence that LEV is realistic
• Specifics the seven types of damage
• Intracellular junk/medical bioremediation
• The Methuselah Foundation

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• Structure of this talk
• Repair versus retardation
• Longevity escape velocity concept
• Some evidence that LEV is realistic
• Specifics the seven types of damage
• Intracellular junk/medical bioremediation
• The Methuselah Foundation

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Aging in a nutshell Product of evolutionary
nelect, not intent Metabolism ongoingly causes
damage Damage eventually causes
pathology Pathology causes more pathology
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Strategies for intervention Gerontology
Geriatrics Metabolism
Damage Pathology
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How to make a car last 50 years -- plan A
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How to make a car last 50 years -- plan B
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Strategies for intervention Gerontology
Engineering Geriatrics Metabolism
Damage Pathology Claim
unlike the others, the engineering approach may
achieve a large extension of human healthy
lifespan quite soon
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• Structure of this talk
• Repair versus retardation
• Longevity escape velocity concept
• Some evidence that LEV is realistic
• Specifics the seven types of damage
• Intracellular junk/medical bioremediation
• The Methuselah Foundation

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• Reasons for the engineering approach
• it targets initially inert intermediates
  (damage)

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• Reasons for the engineering approach
• it targets initially inert intermediates
  (damage)
• repairing damage buys time

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Retarding aging benefits modest
max
Reserve
frail
0
0
Age
Halving rate of damage starting in middle age -
doubles remaining healthspan - raises total
healthspan by maybe 20
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Comparable repair far better
max
hard
Reserve
easy
frail
0
0
Age
Fixing half the damage starting in middle age -
doubles total healthspan - raises remaining
healthspan maybe 5-fold
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Robust human rejuvenation (RHR) Addition of 30
extra years of healthy life (and total life) to
people who are already in middle age when
treatment is begun
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Ever-improving repair better yet
max
very hard
Reserve
hard
easy
frail
0
0
Age
Fixing half the damage, then 3/4 - not as good
as doing 3/4 first time - but better than doing
1/2 first time
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Infinitely better, in fact
max
Reserve
frail
0
0
Age
Fixing half the damage, then 3/4, then 7/8. -
outpaces the so-far-unfixable damage -
maintains healthspan indefinitely
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Longevity escape velocity (LEV) The rate at
which rejuvenation therapies must improve
(following the achievement of RHR) in order to
outpace the accumulation of
so-far-irreparable damage
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• Structure of this talk
• Repair versus retardation
• Longevity escape velocity concept
• Some evidence that LEV is realistic
• Specifics the seven types of damage
• Intracellular junk/medical bioremediation
• The Methuselah Foundation

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Simulating aging (Phoenix de Grey, AGE, in
press) Metabolism ongoingly causes
damage and Damage eventually causes
pathology So. Simulations of aging (and
intervention) should simulate damage accumulation
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• Simulating damage basis
• damage of many types accumulates
• any can kill us (i.e. they are not additive)
• within each type, subtypes are additive
• damage feeds back to hasten more damage
• people differ in damage accumulation rates
• death is from damage X challenge (e.g. flu)

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Simulating damage model Structural
parameters N_CAT The number of damage categories
each person has N_MECH The number of mechanisms
in each category MECH_WEIGHTm The contribution
of a mechanism to a category Fitting
parameters BASAL_M The mean basal damage
rate BASAL_SD The standard deviation of the
basal damage rate BASAL_H The homogeneity of
basal damage rate in a single person EXP_M The
mean exponential damage rate EXP_SD The standard
deviation of the exponential damage rate EXP_H
The homogeneity of exponential damage rate in a
single person FATAL_M The mean yearly
challenge FATAL_SD The standard deviation of the
yearly challenge Values set for each person at
initialisation PB Basal rate for the person
lognorm(BASAL_M, BASAL_SD) PE Exponential rate
for the person lognorm(EXP_M, EXP_SD) MBc,mBasal
rate for each mechanism lognorm(BASAL_M,
BASAL_SD)(1-BASAL_H) PBBASAL_H MEc,m
Exponential rate for each mechanism
lognorm(EXP_M, EXP_SD)(1-EXP_H) PEEXP_H
D_Mc,m Cumulative damage for each mechanism
0 D_Cc Cumulative damage for each category
0 Variables updated for each person at each time
step (year) Total damage PD(t) SUM
c1..N_CAT D_Cc(t) Damage increment
DI_Mc,m(t) MBc,m MEc,mPD(t-1) Cumulative
damage D_Mc,m(t) DI_Mc,m(t)
D_Mc,m(t-1) Cumulative category damage D_Cc(t)
SUM m1..N_MECH DI_Mc,m(t) Fatality
challenge FATAL(t) norm(FATAL_M,
FATAL_SD) If D_Cc(t) gt FATAL(t) for any c, the
person dies at age t
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Validation age at death
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Results how damage evolves
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Results defeat of damage Therapies doubling in
efficacy every 42 y
0 50 100 150
200 250 300 350
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Results LEV in practice Therapies doubling in
efficacy every 42 y
0 50 100 150
200 250 300 350
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LEV decreases with time
max
Reserve
frail
0
0
Age
Fixing half the damage, then 2/3, then 3/4. -
still good enough - just like gravitational
escape velocity
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Data
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• Structure of this talk
• Repair versus retardation
• Longevity escape velocity concept
• Some evidence that LEV is realistic
• Specifics the seven types of damage
• Intracellular junk/medical bioremediation
• The Methuselah Foundation

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• Reasons for the engineering approach
• it targets initially inert intermediates
  (damage)
• repairing damage buys time
• damage is simpler than metabolism or pathology

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Problem 1 this is metabolism
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Problem 2this is the pathology

• Alzheimers
• Stroke
• Sarcopenia
• Osteoarthritis
• Hormonal Imbalance
• Kidney Failure

• Cancer
• Heart Disease
• Diabetes
• Incontinence
• Osteoporosis
• Macular Degeneration

• Parkinsons
• Pneumonia
• Emphysema
• Sex Drive
• and LOTS more

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This is the damage
Seven Deadly Things

1. Junk - Inside Cells
2. Junk - Outside Cells
3. Cells - Too Few
4. Cells - Too Many
5. Mutations - Chromosomes
6. Mutations - Mitochondria
7. Protein Crosslinks

No new type of damage identified since 1982!
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Giving the middle-aged 30 years of
extra healthy life Robust Human
Rejuvenation
Damage rising with age It or its effects reversible by
Cell loss, cell atrophy Cell therapy, mainly
Extracellular junk Phagocytosis by immune stimulation
Extracellular crosslinks AGE-breaking molecules/enzymes
Death-resistant cells Suicide genes, immune stimulation
Mitochondrial mutations Allotopic expression of 13 proteins
Intracellular junk Transgenic microbial hydrolases
Nuclear epimutations (only cancer matters) Telomerase/ALT gene deletion plus periodic stem cell reseeding
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• Structure of this talk
• Repair versus retardation
• Longevity escape velocity concept
• Some evidence that LEV is realistic
• Specifics the seven types of damage
• Intracellular junk/medical bioremediation
• The Methuselah Foundation

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Giving the middle-aged 30 years of
extra healthy life Robust Human
Rejuvenation
Damage rising with age It or its effects reversible by
Cell loss, cell atrophy Cell therapy, mainly
Extracellular junk Phagocytosis by immune stimulation
Extracellular crosslinks AGE-breaking molecules/enzymes
Death-resistant cells Suicide genes, immune stimulation
Mitochondrial mutations Allotopic expression of 13 proteins
Intracellular junk Transgenic microbial hydrolases
Nuclear epimutations (only cancer matters) Telomerase/ALT gene deletion plus periodic stem cell reseeding
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Aggregates major examples - Proteins in
neurodegeneration - Oxysterols in atherosclerosis
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Autophagy in Alzheimers Disease
Dystrophic Neurites
IEM
Calnexin
Cat D
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Endothelial Cells
Lipid-engorged Lysosome
Foam Cell
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• Bioremediation the concept
• - Microbes, like all life, need an ecological
  niche
• - Some get it by brawn (growing very fast)
• - Some by brain (living off material than others
  can't)
• Any abundant, energy-rich organic material that
  is hard to degrade thus provides selective
  pressure to evolve the machinery to degrade it
• - That selective pressure works. Even TNT, PCBs

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Example DGGE Results from Perchlorate-Reducing,
Membrane Biofilm Reactors
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Xenocatabolism the concept Graveyards -
are abundant in human remains - accumulate
bones (which are not energy-rich) - do not
accumulate oxysterols, tau etc... - so,
should harbour microbes that degrade them -
whose catabolic enzymes could be therapeutic
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Environmental decontamination in vivo
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7-ketocholesterol degradation - a good start
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7-KC degradation - presented at meetings
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First MF-funded paper submitted
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• Steps to biomedical application
• Isolate competent strains select by starvation
• Identify the enzymes (mutagenesis, chemistry,
  genomics)
• Make lysosome-targeted transgenes, assay cell
  toxicity
• Assay competence in vitro (more
  mutagenesis/selection)
• Construct transgenic mice, assay toxicity in vivo
• Assay competence in disease mouse models
• Test in humans as for lysosomal storage diseases

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• Structure of this talk
• Repair versus retardation
• Longevity escape velocity concept
• Some evidence that LEV is realistic
• Specifics the seven types of damage
• Intracellular junk/medical bioremediation
• The Methuselah Foundation

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• Funds current status
• 4.5M in Mprize pot
• Research pot being spent as fast as we fill it
• LysoSENS being funded (100k/yr) by 2005-2006
  donations to the MF
• MitoSENS being funded (150k/yr) by Peter
  Thiels donation of 500k
• Thiels challenge pledge (3M) is 12 our next
  goal is to match it in full (i.e. raise 6M)

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• Eventual organisational structure
• Medium-term goal proof of concept in mice
• Strategy solve/combine subgoals (SENS)
• Procedure
• implement subgoals 350 people
• scientifically interesting and respected
• best done extramurally by academics
• combine in same mice 150 people
• scientifically tedious and unrewarded
• best done in-house by paid technicians

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• Ramping up.
• Level 1 funding of up to 300k per year
  guaranteed for at least 3 years. (This is where
  we are now.) Selected SENS strands supported at
  entry level (1 project/strand, 1-2 FTEs/project)
• Level 2 funding of 300k-3m per year, three
  years. (This is where we will be when the Thiel
  pledge is fully matched.) Six SENS strands
  supported at minimal level (1-3 projects/strand,
  1-3 FTE/project)

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• Ramping up.
• Level 3 funding of 3M-20M per year guaranteed
  for at least five years. Grant applications
  solicited 30-100 FTEs funded, across up to 30
  projects
• Level 4 funding of 20M-100M per year, ten
  years. Physical facility (Institute for
  Biomedical Gerontology) set up (50-150 FTEs)
  extramural research support as in Level 3
  (100-350 FTEs)

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Why I am doing this
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Why I am doing this
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• Why I am doing this
• I offer no apology for using media interest in
  life extension to make the biology of ageing an
  exception to Plancks observation that science
  advances funeral by funeral lives, lots of them,
  are at stake.
• de Grey 2005, EMBO Reports 6(11)1000

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Shameless plug
Out now 17.79 at Amazon